15, 16 substituted steroids and derivatives

ABSTRACT

Compounds of the formula   ARE DESCRIBED. The aforesaid compounds are useful as hormonal agents.

United States Patent Furst et al.

[4 1 July 11,1972

l5, l6 SUBSTITUTED STEROIDS AND DERIVATIVES Andor Furst, Basel; PeterMuller, Arlesheim; Marcel Muller, Frenkendorf; Dieter Kagi, Basel, allof Switzerland Assignee: Hoffman-La Roche Inc., Nutley, NJ.

Filed: April 17, 1969 Appl. No.: 817,178

Inventors:

Foreign Application Priority Data April 22, l968 Switzerland ..5935/68U.S. Cl ..260/397.3, 260/397.4, 260/397 .47

Int. Cl ..C07c 169/32, C07C 169/34 Field of Search ..260/397.3, 397.4

References Cited UNlTED STATES PATENTS 4/1969 Edwards ..260/239,55

Primary Examiner-Elbert L. Roberts Attorney-Samuel L. Welt, Jon S. Saxe,Bernard .8. Leon, William l-l. Epstein, George M. Gould and Edward L.Mandell [57] ABSTRACT Compounds of the formula C HzRll are described.The aforesaid compounds are useful as hormonal agents.

34 Claims, No Drawings l5 l6 SUBSTITUTED STEROIDS AND DERIVATIVES BRIEFDESCRIPTION OF THE INVENTION The present invention relates to steroidcompounds of the formula 5 cilHrRzi C=O H1O I Rna wherein R is aB-ketQ-A a S-keto-A, a 3-ketoA, a 3- 2O keto-A a B-acylOXy-A a3-acyloxy-A a 3-acyl0xy-A a 3o-alkoxy-A' or a 3-alkoxy-A system; R ishydrogen or halogen; R is hydrogen, halogen or lower alkyl; R is ahydroxy, acyloxy or alkoxy group; R is hydrogen, halogen, hydroxy,acyloxy or alkoxy and both residues R in each case is hydrogen ormethyl.

As used herein the term acyloxy group shall mean a group which containsthe residue of a saturated or unsaturated aliphatic, cycloaliphatic,araliphatic or aromatic carboxylic acid with up to carbon atoms,preferably up to 12 carbon atoms. Examples of such acids include formicacid, acetic acid, pivalic acid, propionic acid, butyric acid, caproicacid, oenanthic acid, oleic acid, palmitic acid, stearic acid, succinicacid, malonic acid, citric acid or benzoic acid.

The term alkoxy group" includes groups containing up to 10 carbon atomswhich maybe aliphatic, cycloaliphatic or araliphatic in nature. Examplesof such alkoxy groups include methoxy, ethoxy, propoxy, butoxy andisomers such as tertiary butoxy. cyclopentyloxy, cyclohexyloxy andbenzyloxy.

As used herein, the term lower alkyl" comprehends a 40 straight orbranched chain hydrocarbon group containing from one to five carbonatoms. Examples of lower alkyl groups include methyl, ethyl, propyl,isopropyl, butyl and the like. The term "halogen includes fluorine,chlorine, bromine, and iodine with fluorine, chlorine and bromine beingthe halogens of preference.

In one preferred aspect of the present invention compounds of formula Iare defined wherein R is hydrogen, that is, compounds corresponding tothe following formula wherein R R R R and R are as above.

In another preferred aspect of the present invention, compounds offormula I are defined wherein R is methyl, that is where R R R R and Rare as above.

Particularly preferred groups of compounds are obtained when R is a ketogroup in conjunction with a A, A, N- or A system and R and R arehydrogen, that is compounds of the following formulas and Id where Rm,is as above; V is a saturated or unsaturated bond between the l and 2positions; W is a saturated or unsaturated bond between the 6 and 7positions and R is hydrogen or halogen.

HaC 9H I Re where R, R R and R are as above;

8. Halogenation in the 2-position of a compound of the following formulaRe III arwhere R, R5, R R2. and W are as above;

C. Halogenating in the 6 position a steroid of the formula where R, R RR V and W are as above;

C Alkylating in the 6-position a steroid of formula IV above;

E. Hydroxylating in a manner known per se in the 2l-position a steroidof the formula 5 where R, R R R and R are as above;

F. Dehydrogenating in the l-and/or 6-position a steroid of the formulawhere R, R R R and R are as above; G. Enol-esterifying orenol-etherifying a steroid of the formula H. Acylating or alkylating asteroid of formula 1 wherein at least one substituent group R or R is ahydroxy group; or,

1. Hydroxylating in the l7a-position a steroid of the formula wherein R,11,, R R V and W are as above; or K. isomerizing the -methylene group ina steroid of formuemit Hgc

wherein R, R R and R are as above, to form a 6-methyl group.

The oxidation of the 17(20) double bond to the hydroxyketone grouping(procedure A) can, for example, be carried out using oxidizing agentssuch as a tertiary amine N-oxide peroxide in tert.-butanol/pyridine inthe presence of catalytic amounts of osmium tetroxide. Examples oftertiary amine N- oxide peroxides include for example,N-methyl-morpholine N- oxide peroxide or triethylamine oxide peroxide.On the other hand, with oxidizing agents such as osmium tetroxide orpermanganates one can oxidize to the 17,20-glycol and further oxidizethe latter to the hydroxyketone with oxidizing agents such as chrornicacid.

The halogenation of the steroid of formula III or its 6(7)- dehydroderivative in the 2-position (procedure 13) can be accomplished, forexample, as follows:

With a reducing agent such as lithium aluminum hydride, the startingsteroid of formula III or its 6(7)-dehydro-derivative is reduced to thecorresponding 3,20-diol. The 3,20-diol can be partially oxidized (e.g.,by means of manganese dioxide) to the 3-keto-20-ol-steroid. Thiscompound is converted into the 2-oxalyl or 2-hydroxymethylene compoundby reaction with an oxalic acid or formic acid ester (e.g., the ethylester) and then treated with halogenating agents such as perchlorylfluoride, N-bromoor N-chlorosuccinimide or elementary chlorine, bromineor iodine and a base such as an alkali alcoholate. Oxidation of theZO-hydroxy group with oxidizing agents such as chrornic acid finallyyields the.2-halo derivative of a compound of formula II] or of its 6( 7)-dehydro derivative.

The halogenation of a steroid of formula IV or of its 6(7)- dehydroderivative in the 6-position (procedure C) can be effected by reactionwith a halogenating agent such as an N- haloimide (e.g.,N-bromosuccinimide) or with a halogen (e. g., with elementary bromine).[See .I. Am. Chem. Soc. 72, 4534 (l950)]6-position can also beaccomplished by convening a steroid of fonnula IV into a 3-enol ester or3-enol ether (e.g., the 3-enol acetate) and thereafter reacting withchlorine or bromine [see .1. Am. Chem. Soc. 82, 1230 1960)]; with aN-haloimide [see .1. Am. Chem. Soc. 82, 1230 (1960); 77, 3827 (1955)] orperchloryl fluoride [see J. Am. Chem. Soc. 81, 5259 (1959); Chem. and1nd. 1959, 1317].

A further procedure for halogenation in the 6-position comprisesconverting a 6(7)-dehydro or 1(2), 6(7)-bisdehydro derivative of asteroid of formula IV into the 6,7-oxide (which can, for example, bebrought about by treatment with peracids such as perphthalic acid),treating the 6,7-oxide with hydrogen halide and splitting off water fromthe 7-hydroxy-6- halo-steroid thus obtained, with elimination of the7-hydroxy group and introduction of a 6(7) double bond.

Insofar as isomer mixtures (i.e., mixtures of 6aand halo-steroids) areformed in the halogenations described hereinbefore, these can beseparated into the pure isomers according to known methods such aschromatography.

For the alkylation of a steroid of formula IV (procedure D), one canproceed as follows: A steroid of formula IV is treated with a ketalizingagent such as a glycol, preferably ethylene glycol, in the presence of acatalyst such as p-toluenesulfonic acid. On treatment with a peracidsuch as perphthalic acid, the ketalized steroid yields a5,6-oxido-steroid. Reaction of this 5,6-oxido-steroid with an alkylGrignard compound, the alkyl group of which corresponds to the alkylgroup which is to be introduced into the 6-position, and subsequenttreatment with acid yields, with dehydration and ketal-cleavage, a6-alkyl derivative of the starting steroid of formula IV.

The hydroxylation of a steroid of formula V in the 2l-position(procedure E) can, for example, be effected by preparing the 2l-diiodideby treatment with iodine and a base such as calcium oxide in methanol,and reacting this with potassium acetate in glacial acetic. The2l-acetoxy compound thus obtained can then be saponified (e.g. withaqueous-methanolic potassium carbonate solution).

The introduction of a A double bond into a steroid of formula Vl(procedure F) can, for example, be effected in the 6,7-position with asubstituted benzoquinone such as chloranil [see J. Am. Chem. Soc. 82,4293 (1960); 81, 5951 (1959)] or with2,3-dichloro-5,6-dicyanobenzoquinone or with manganese dioxide [see J.Am. Chem. Soc. 75, 5932 1953) The introduction of a A double bond into asteroid of formula VI can, for example, be brought about in thel,2-position in a microbiological manner or with dehydrogenating agentssuch as iodine pentoxide, periodic acidor selenium dioxide [see J. Am.Soc. 81, 1235; 5951 (1959) with 2,3-dichloro-5,6- dicyanobenzoquinone[see Proc. Chem. Soc. 1960, 14] with lead tetraacetate [see J. Am. Chem.Soc. 77, 661 (1955)] or with chloranil [see J. Am. Chem. Soc. 82, 4293(1960)]. With 2,3-dichloro-5,6-dicyanobenzoquinone or chloranil, the1,4,6 trisdehydro compound can be obtained directly from a steroid offormula VI.

The enol-etherification of steroids of formula VI] or their 6(7)-dehydroderivatives (procedure G) for the purpose of introducing the 3-alkoxy-Aor the 3-alkoxy-A system can, for example, be undertaken by reactionwith an alcohol (e.g., methanol, ethanol, benzyl alcohol) in thepresence of a catalyst (e.g., p'toluenesulfonic acid) or with anorthoformic acid ester in the presence of a catalyst (e.g. withorthoformic acid ethyl ester and hydrochloric acid) or with adialkoxypropane (e.g., 2,2-dimethoxypropane) in methanoldimethylformamide in the presence of a catalyst (such asptoluenesulfonic acid).

The enol-esterification of 3-keto-A steroids of formula VI] or their6-dehydro derivatives to 3-acyloxy-A or -3-acyloxy-A "'-steroids can beaccomplished by treatment with an acylating agent such as isopropenylacetate in the presence of a catalyst such as p-toluenesulfonic acid.3-Acyloxy-A=""" -steroids of formula I can be obtained by treatment of6'dehydro derivatives of 3-keto N-steroids of formula Vll with anacylating agent such as acetyl chloride/acetic anhydride, optionally inthe presence of a strong acid such as perchloric acid.

The acylation or alkylation of free hydroxy groups in the l7aor2l-position of a steroid of formula I (procedure H) can be effected in amanner known per se by treatment with an acylating agent such as an acylchloride (e.g., acetyl chloride) or by treatment with an alkyl halidesuch as methyl or ethyl iodide or an alkyl sulfate such as dirnethylsulfate in the presence of an acid-binding agent such as pyridine.

The l7a-hydroxylation of a steroid of formula VIII (procedure I) can becarried out as follows:

In a suitable solvent such as dioxane or tert. butanol, a steroid offormula VIII is treated with oxygen in the presence of potassiumtert.-butylate a l7a-hydroperoxide being obtained. The 3- and ZO-ketogroups are thereafter protected (e.g., by ketalization) and thel7a-hydroperoxlde group is reduced to the hydroxy group e.g., with areducing agentsucllaszlne).

The isomerization of the 6-methylene group of a steroid of formula IX(procedure K) can be effected by treatment of the starting steroid witha catalyst, e.g., a hydrogenation catalyst such as palladium.Conveniently, a hydrogen donator, such as cyclohexene, is added as anactivator for the catalyst. Undesired side-reactions such ashydrogenation caused by the hydrogen donator can be suppressed bybufi'ering the reaction mixture.

The starting compounds of formula II can be prepared as follows;

A 3fi-hydroxy-androsta-5J 5-dien-l7-one is converted intoBl6B-methylene-pregn-4-ene-3,20-dione,

the 3B-acetate by acetylation (e.g., with pyridine/acetic anhydride). Amethylene or isopropylidene group is then added at the l5, 16 doublebond of a 3B-acetoxy-androsta-5,l S-dienl7-one thus obtained. This canbe brought about by treating the steroid with dimethylsulfoxoniummethylide or, for the purpose of adding the isopropylidene group, withdiphenylsulfonium isopropylide [see'J. Am. Chem. Soc. 89, 3912 (1967)Re-acetylation with pyridine/acetic anhydride gives a 3B- acetoxyl S l6-methylene (or isopropylidene )-androst-5-enl7-one which is convertedaccording to Wittig with an ethylidene phosphorane into a3B-acetoxy-l5,16-methylene (or isopropylidene)-pregna-5,l7(20) diene.Alkaline hydrolysis and Oppenauer oxidation of such a compound yields a15,16- methylene (or isopropylidene )-pregna-4,l7-dien-3-one of formulaII. Insofar as they are not already present, halogen or alkylsubstituents can be inserted into a starting compound of formula ll thusobtained in the positions 2 or 6, for which the methods described abovein relation to the halogenation or alkylation of steroids of formulasIII and IV can be used. Compounds of formula II with halogensubstituents are preferably manufactured in this manner.

Compounds of formula [X can be prepared by reacting a steroid of formulaI wherein R is hydrogen and R is a 3-3- methoxy-N" -system in a mannerknown per se to form a corresponding 6-formyl derivative, reducing theformyl group, e.g. by means of sodium borohydride, to form ahydroxymethyl group and finally dehydrating the reaction product withconcomitant cleavage of the enol ether group.

The compounds of formula I possess hormonal (e.g., progestative)activity and influence the gonadotropin economy. They can be used asmedicaments (e.g., for the treatment of menstruation anomalies and forfertility control). As a dosage guideline, a daily dosage of 1-10 mg.may be employed for a mature subject. it should be noted that higher orlower dosages can be used depending on the individual needs and theprofessional judgment of the person administering or supervising theadministration of the subject compounds.

The compounds of this invention can be used in the form ofpharmaceutical preparations which contain them in admixture with apharmaceutical organic or inorganic inert carrier material which issuitable for enteral, percutaneous or parenteral application such as,for example, water, gelatin, gum arabic, lactose, starches, magnesiumstearate, talc, vegetable oils, polyalkyleneglycols, Vaseline, etc. Thepharmaceutical preparations can be submitted in solid form (e.g., astablets, dragees, suppositories, capsules), in semi-solid form (e.g., asointments) or in liquid form (e.g., as solutions, suspensions, oremulsions). The may be sterilized and/or contain additives such aspreserving, stabilizing, wetting or emulsifying agents, salts forvarying the osmotic pressure or buffers. They can also contain yet othertherapeutically valuable substances.

The following examples are illustrative but not limatative of thisinvention. All temperatures are stated in degrees Centigrade.

EXAMPLE 1 A total of ml. of a 0.65 molar solution of N-methylmorpholineoxide peroxide were added dropwise within 10 minutes at room temperatureto a well stirred mixture of 7.0 g. of 1513, 16B-methylene-pregna-4,l7(20)-dien-3-one, 70 ml. of methylene chloride, ml.of abs. tert. butanol, 12 ml. of pyridine and 225 mg. of osmiumtetroxide. The mixture was stirred at room temperature for 3 hours,subsequently treated with 2.3 g. of sodium sulfite and again stirred for30 minutes. For the working up, the reaction mixture was poured ontoicewater and extracted with methylene chloride. The organic extractswere washed with water and dried with sodium sulfate. The crude productobtained after evaporation of the solvent was chromatographed on 400 g.of silica gel. The hexaneether (2:1) eluates yielded 4.3 g. of purel7B-hydroxy-l5 melting point 190l91(from acetone-hexane). [01],, =++100(c= 0.1 in dioxane). UV spectrum: 6 1 17,200. The ether eluates gave 1.2g. of pure 17a, 20dihydroxy-l5B,l6/3-methylenepregn-4-en 3-one, meltingpoint 192-1 96 (from acetone-hexane). e 16,700. [a],," 37 (c 0.1 indioxane). lSfi,l6B4,17(20)-dien-3-one can be prepared as follows:

A total of 2.83 g. of a 50 percent suspension of sodium hydride inmineral oil was added to a solution of 12.3 g. of trimethylsulfoxoniumiodide in 250 ml. of dimethyl sulfoxide. The mixture was stirred underargon for 10 minutes, then treated within minutes with a solution of17.5 g. of 3,13- acetoxy-androsta-5,l5-dien-l7-one (prepared byacetylation of 3-hydroxy-androsta-5,l5-dien-17-one)in 400 ml. ofdimethylsulfoxide and subsequently stirred at room temperature for 4hours. For the working up, the mixture was poured onto ice-water,acidified with acetic acid and extracted with methylene chloride. Theorganic extracts were washed neutral with water, dried with sodiumsulfate and the solvent evaporated in vacuum. The residue was treatedfor 2 hours at room temperature with 250 ml. of pyridine and 250 m1. ofacetic anhydride, thereafter evaporated to dryness in vacuum andchromatographed on 200 g. of aluminum oxide (Act. II). The benzeneeluates yielded 16.0 g. of thin-layer chromatographically pure3/3-acetoxy-1Sfi,l6B-methylene-androst-5- en-l 7-one which melted at142-143 after crystallization from acetone-hexane. [0],, 98 (c=0.l indioxane).

To a solution of 15.2 g. of3Bacetoxy-l53,16/3-methy1eneandrost-5-en-17-one in 260 ml. of dimethylsulfoxide there were added 82.4 g. of triphenylethylphosphonium bromideand thereafter, with stirring and argon-gassing withing 15 minutes, asolution of 24.8 g. of potassium tert. butylate in 400 ml. of dimethylsulfoxide. The phosphonium salt went into solution with red colorationand slight increase in temperature. The reaction mixture was stirred atroom temperature for 2 hours and then at 60 for a further 3 hours. Forthe working up, the mixture was poured onto ice-common salt solution andextracted with ether. The ether extracts were washed neutral with water,dried with sodium sulfate and evaporated to dryness in vacuum. Theresidue was dissolved in 150 ml. of pyridine and, after the addition of150 ml. of acetic anhydride, allowed to stand at room temperature for 3hours. The mixture was thereafter evaporated to dryness in vacuum. Theresidue, which contains major amounts of triphenylphosphine oxide wasdissolved in hexane-acetone (8:1) and the solution was filtered through800 g. of silica gel. The filtrate yielded 14.8 g. of pure 3/3-acetoxy-l5B,l6/3-methylene-pregna-SJ7 ()-diene, melting point 145-146 (fromethanol). [01 94 (c= 0.1 in dioxane).

A mixture of 12.5 g. of3B-acetoxy-1SBJGB-methylenepregna-5,'l7(20)-diene, 100 ml. of dioxane,500 m1. of methanol and 12.5 g. of potassium carbonate was stirred atroom temperature under argon-gassing for 3 hours, thereafter poured ontoice-water and extracted with methylene chloride. The organic extractswere washed with water, dried with sodium sulfate and the solventevaporated in vacuum. A total of 10.0 g. of pure3B-hydroxy-l5B,l6B-methylene-pregna-5,l7 (20)-diene, melting point180-l82 (from acetone), was obtained [01],, =95 (c=0.l dioxane).

A total of 10.0 g. of 3B-hydroxy-l53,16B-methylenepregna-5,l7(20)-dienewas dissolved in 1,400 ml. of toluene and 1,000 m1. of cyclohexanone.Toluene (200 ml.) was first of all distilled 05 from this solution. Atotal of 50.0 g. of aluminum tert-butylate was subsequently added andthe mixture heated under reflux at 140 with argon-gassing for 2 2%hours. For the working up, the mixture was poured onto ice-water andextracted with methylene chloride. The organic extracts were washed withwater, dried with sodium sulfate and the solvent evaporated in vacuum.The residue was subjected to a steam-distillation for 1 hour. Thedistillation residue was extracted with ether The ethereal extractsyielded 9.5 g. of crystalline material which, crystallized fromacetone-hexane,

yielded 7.5 g. of pure 156,16Bmethylene-pregna-4,l7(20)- dien-3-one.Melting point l181. [a] +92 (0 0.1 in dioxane).

EXAMPLE 2 A total of 6 ml. of a 0.65-molar solution ofN-methylmorpholine oxide peroxide was added dropwise at room temperaturewithin 10 minutes to a well stirred mixture of 500 mg. of21-acetoxy-15B,16B-methy1enepregna-4,l 7(20)-dien-3- one, 5 ml. ofmethylene chloride, 10 ml. of abs. tert. butanol, 0.75 ml. of pyridineand 14 mg. of osmium tetroxide. The mixture was stirred at roomtemperature for 3 hours, 150 mg. of sodium sulfite were subsequentlyadded and the mixture was again stirred for 30 minutes. The reactionmixture was poured onto ice-water and extracted with methylene chloride.The extracts were washed with water, dried over sodium sulfate andevaporated. Chromatography of the crude product thus obtained on a -foldamount of Kieselgel with hexane/ether 1:1 gave pure21-acetoxy-17a-hydroxy-l 5,8,16flmethylenepregn-4-ene-3,20-dione.

2l-Acetoxy-158,16B-methylene-pregna-4J 7(20)-dien-3- one can be preparedas follows: 1

A total of 2 g. of l5B,16B-methyleneandrost-4-ene-3,17- dione wasdissolved in 10 ml. of dimethylforrnamide and, after the addition of 10ml. of 2,2-dimethoxy-propane, 50 mg. of ptoliiene-sulfonic acid and 0.4ml. of methanol, boiled at reflux under argon for 3 hours. Aftercooling, the solution was treated with 300 mg. of sodium bicarbonate,allowed to stand for 10 minutes and then poured onto water. The mixturewas extracted with ether which contained a few drops of pyridine, theextracts were washed with water, dried over sodium sulfate and thesolvent evaporated. Crystallization from a little abs. alcohol whichcontained 1 percent pyridine gave pure 3-methoxy-15B,16B-methyl-eneandrosta-3,S-dien-17-one.

A total of 1.2 g. (25 mmol) ofa 50 per cent sodium hydride suspension inmineral oil was washed free of oil with n-hexane. The sodium hydride wasthereafter suspended in 60 ml. of 1,2- dimethoxyethane and treateddropwise under an argon atmosphere with stirring with 5.6 g. (25 mmol)of triethylphosphonoacetate. After standing for an hour at roomtemperature, a solution of 1.56 g. (5 mmol) of 3-methoxy-15B,16B-methyleneandrosta-3,5-dien-l7-one in 10 ml. of 1,2-dimethoxyethane was added dropwise. The mixture was stirred at roomtemperature for 30 boiled at reflux for 1 hour, the cooled solution waspoured onto ice-water and the product extracted with ether. The extractswere washed with water, dried over sodium sulfate and evaporated. Thecrude 3- methoxy-l5B,16B-methylenepregna-3,5,16(20)-triene 21-carboxylic acid ethyl ester thus obtained was employed in the nextreaction without further purification.

A total of 1.6 g. of crude 3-methoxy-l5B,l6B- methy1enepregna-3,5,17(20)-triene 2l-carboxylic acid ethyl ester was dissolved in 100 ml. ofabs. ether and added dropwise under argon to a stirred suspension of 2g. of lithium aluminum hydride in 50 ml. of ether. The mixture wasfirstly stirred at room temperature for 30 minutes, the at reflux for 2hours, and the reaction mixture cooled to 0 was then decomposed bydropwise addition of water. The organic phase was decanted and thepaste-like residue triturated several times with methylene chloride andwater. The combined liquid phases were washed neutral with saturatedcommon salt solution, dried over sodium sulfate and evaporated. Thecrude 21- hydroxy-3-methoxy-l 5B, 1 6B-methylenepregna-3 ,5 ,17(20)-triene was employed in the next step without purification.

A total of 1.2 g. of crude 2l-hydroxy-3-methoxy-l55,163-methylene-pregna-3,5,l7(20)-triene was dissolved in 20 ml. of dioxaneand, after the addition of 1 ml. of concentrated hydrochloric acid and 1ml. of water, stirred under argon at room temperature for 2 hours. Thereaction mixture was then poured onto a large amount of water, extractedwith ether/methylene chloride 3:1 the extracts washed with saturatedbicarbonate solution and saturated common salt solu tion, dried oversodium sulfate and he solvent evaporated. The crude product waschromatographed on a 100-fold amount of Kieselgel. Pure 2 l -hydroxy-l53,1 68- methylenepregna-4,l7(20)-dien-3-one was isolated withhexane/acetone (5:1).

A total of 500 mg. of 2l-hydroxy-l5B,16B- methylenepregna-U7(20)-dien-3-one was treated with 5 ml. of pyridine and 5 ml. of aceticanhydride and allowed to stand overnight. The excess acetic anhydridewas decomposed by the addition of methanol and the reaction mixtureevaporated in vacuum. Crystallization from acetone/hexane gave pure 21-acetoxy- 1 5/3, l6B-methylenepregna-4, l 7( 20)-dien-3-one.

EXAMPLE 3 A total of 4.05 g. of17a-hydroxy-l5B,l6B-methylenepregn-4-ene-3,20-dione and 0.40 g. ofp-toluenesulfonic acid were dissolved in 160 ml. of benzene. Benzene (25ml.) was distilled off from the reaction mixture. A mixture of 40 ml. ofisopropenyl acetate and 80 ml. of benzene was then added during 12 hourswhile 120 ml. of benzene was simultaneously distilled off via a Vigreuxcolumn. The cooled reaction solution was treated with benzene, washedwith cold sodium bicarbonate solution and water and dried with sodiumsulfate. After evaporation of the solvent in vacuum, the crude productwas dissolved in benzene-ether (95:5) and filtered through 90 g. ofsilica gel. The eluate yielded 4.8 g. of pure 3,17a-diacetoxy-l53,16/3-methylene-pregna-3,5-dien-20-one which melted at l59-l62 afterrecrystallization from methanol. e =l5,100 [al ==1 18 (c=0.l indioxane).

EXAMPLE 4 A solution of 0.85 g. of chlorine gas in 30 ml. of glacialacetic was added within 5 minutes to a cooled (-5), well stirred mixtureof 4.70 g. of 3,17a-diacetoxy-15B,16B- methylene-pregna-3,S-dien-ZO-one,8.8 g. of potassium acetate, 200 ml. of ether, 85 ml. of glacial aceticand 15 ml. of water. The mixture was subsequently stirred at -5 for afurther 10 minutes, then poured onto ice-water and extracted with ether.The ether extracts were washed neutral with water, dried with sodiumsulfate and evaporated to dryness. The residue was chromatographed onsilica gel. With hexane-ether (2:1 there was firstly eluted17a-acetoxy-2Bchloro-l 53,165 methylene-pregna-4-ene-3,20-dione whichwas recrystallized from acetone-hexane. Melting point 225226. e 16,000.a ,,=-129.

The following hexane-ether 2:1 eluates yielded pure17aacetoxy-6B-chloro-l 53,16fi-methylene-pregn-4-ene-3,20- dione.Melting point 154155 (from ether-isopropyl ether). e 15,600 [011 =92(c==0.l in dioxane).

EXAMPLE A solution of 1.35 g. of l7a-acetoxy-6fi-chloro-l 513,165-methylene-pregna-4,6-diene-3,20-dione, 65 mg. of p-toluenesulfonic acidand 1.2 ml. of orthoformic acid ethyl ester in 30 ml. of dioxane wasallowed to stand in the dark for 16 hours and then was added withinminutes to a well stirred mixture of 7.0 g. of manganese dioxide, 60 ml.of glacial acetic and 5 ml. of water. The mixture was stirred for afurther 2 hours, poured onto ice-water and extracted with methylenechloride. The organic extracts were washed with sodium carbonatesolution and water, dried with sodium sulfate and evaporated. Theresidue was chromatographed on silica gel. The thin-layerchromatographically uniform fractions eluted with hexaneether (2:1) werecombined and yielded, when recrystallized from ether, pure17a-acetoxy-6-chlorol5,6,l6B-methylene= pregna-4,6-diene3,20-dione ofmelting point 235- -237. e 22,700 [a],,=- 102 (c 0.1 in dioxane).

EXAMPLE 6 A solution of l g. of calcium chloride in 10 ml. of abs.methanol was added to a mixture of 10.0 g. of 17a-hydroxy-15,6,l6fi-methylene-pregn-4-ene-3,20-dione and 50 ml. of abs.

methanol. After the addition of 6.0 g. of calcium oxide (dried at 600),a solution of 14.8 g. of iodine in 55 ml. of abs. methanol whichcontained 6 per cent calcium chloride was added dropwise with stirringand nitrogen-gassing at 25-27 in the dark in such a way that thetemperature did not exceed 28 C and the iodine was continuouslyconsumed. After completed addition, the mixture was stirred at roomtemperature for a further 5 minutes and then cooled to l0. Theprecipitate which separated out was filtered off by suction, washed witha little cold (20) methanol and then sucked dry. This material wasintroduced with stirring into a mixture of 180 ml. of ice-water and 15ml. of glacial acetic and stirred at 0 for 30 minutes. It was againfiltered off by suction, washed free from iodine with water and dried at25 in vacuum. There was obtained 17.5 g. of crude diiodide which washeated to reflux under argon-gassing for 2 hours with ml. of acetone,1.5 ml. of water, 1.5 ml. of glacial acetic and 16 g. of potassiumacetate. The cooled reaction solution was poured onto ice-water. The21-acetoxy-l7a-hydroxy-15B,16,B -methylene-pregn-4-ene-3,20-dione wasfiltered off by suction, washed with water, dried in vacuum at 25, andfinally dissolved in ml. of methanol. The solution was treated with asolution of 2.0 g. of potassium carbonate in 35 ml. of water and, whilepassing nitrogen through, stirred at room temperature for 1 lhours. Atotal of 4 ml. of glacial acetic and 10 ml. of water were then added andthe whole mixture poured onto saturated common salt solution. Themixture was extracted with methylene chloride, the extract washed withwater and dried with sodium sulfate. After evaporation of the solvent,there was obtained 9.0 g. of crystals which were chromatographed onsilica gel. Pure l7a,21-dihydroxy-155,165-methylene-pregn-4-ene3,20-dione was eluted with methylenechlorine-acetone (10:1). UV: e 16,800. Melting point l96-198; [a],,=+91.

EXAMPLE 7 A solution of 5.25 g. of 3,l7a-diacetoxy-l5l3,l 6B-methylene-pregna-3,S-diene in 160 ml of acetic acid and 40 ml 2Nhydrochloric acid, was maintained at room temperature for 5 hours. Theproduct was worked up by pouring into icewater, extracting with ether,washing the ethereal extract with sodium carbonate solution and water,drying over sodium sulphate and evaporating. The residue wasrecrystallized from acetone-isopropylether. The l 7a-acetoxy-l 53,1 63-methylene-pregnal-ene-3,20-dione melted at- 244247 C e 17,800; [a],,=-14(c=0.l in dioxan).

EXAMPLE 8 20 g of l7a-acetoxy-l5B,l6/3-methylene-pregna-4-ene-3,20-dione, 1.3 ml of dimethylformamide, 1.2 ml of 2,2 dimethoxypropane,36 mg of p-toluenesulphonic acid and 0.36 ml of methanol were refluxedunder argon for two hours. The product was worked up by pouring thereaction mixture into 100 ml of ice-cold sodium carbonate solution andextracting with ether-methylene chloride. The organic extracts werewashed with water, dried with sodium sulphate and evaporated. Theresidue was recrystallized from methylene chloride-isopropylether. Theproduct was pure l7a-acetoxy-3 -methoxy-1 513,16B-methylene-pregna-3,5-diene-20-one having a melting point of 252253 C.e 21,000 [a],, -205 ((=0.l in dioxane).

EXAMPLE 9 A solution of 2.34 g of 2,3-dichloro-5,6-dicyanobenzoquinonein 100 ml of dioxane, which contained 6.5 percent HCl, was addeddropwise over 3 minutes to a solution of 3.3 g of l7a-acetoxy-l513,16B-methylene-pregna-4-ene-3.20-dione in 100 ml of dioxane whichcontained 6.5 percent BC]. The reaction mixture was stirred for 1minutes, poured into ice-water and extracted with ether-methylenechloride. The organic extracts were extracted three times withdilutesodium hydroxide, washed with water, dried with sodium sulphateand evaporated. The residue was chromatographed on silica gel usingether-hexane as the solvent. The fractions which were uniform accordingto thin layer chromatography were collected and recrystallized fromacetone-hexane. The product was pure17a-acetoxy-1519,16B-methylene-pregna-4,6-diene- 3,20-dione having amelting point of 225-226 C. e =27,000 [a],, '=-86 01 in dioxane).

EXAMPLE l0 10 ml of ethanol containing 0.5 percent cyclohexane was addeddropwise over 5 hours to a stirred, refluxing, mixture of 0.5 g ofl7a-acetoxy-6;l 5B,16B-dimethylene-pregna-4-ene- 3,20-dione, 250 mg ofsodium acetate, 25 mg of 5 percent palladium on carbon and 15 ml ofethanol. The reaction mixture was then filtered and the filtrate wasevaporated. The resulting product was chromatographed on 75 g of silicagel. Elution with hexane-ether provided purel7a-acetoxy-6-methyll53,16B4,6-diene-3,20-dione. After recrystallizationfrom acetone-hexane the product had a melting point of 19ll92 C. e23,500, [01],} =78 (c= 0.1 in dioxane).

EXAMPLE 1 l A freshly prepared solution of 2.0 g of phosgene in 30 ml ofethylene chloride was added over 30 minutes to a stirred, cooled (0 C)mixture of 9.0 g dimethylformamide and 10 ml of ethylene chloride. 10minutes later a solution of 6.0 g of l7a-acetoxy-3-methoxy-l513,16B-methylene-pregna-3,5- diene-20-one in 50 ml of ethylenedichloride which also contained 0.5 ml of pyridine was added. Stirringwas continued for a further 2 hours at l0-15 C. The product was workedup by adding 4 ml of saturated sodium acetate solution, stirringintensively for 10 minutes, pouring into water and extracting withether. The etheral extract was washed several times with water, driedwith sodium sulphate and evaporated under a vacuum. The resulting crude6-formyl-3-enol ether was dissolved in 80 ml of methanol. 0.8 g ofsodium borohydride was then added and the mixture was stirred forminutes at room temperature. The reaction mixture was then poured intoice-water and extracted with methylene chloride and evaporated. Theresulting crude 6-hydroxymethyl-3-enolether was dissolved in 70 ml of 80percent acetic acid and treated at 100 C for minutes. The product wasworked up by pouring into ice-water and extracting withmethylene-chloridepetroleum ether. The organic extracts were washed withsodium carbonate solution and ice-water, dried with sodium sulphate andevaporated. The fractions which were uniform according to thin layerchromatography were collected and, after recrystallization fromacetone-hexane, gave pure 17aacetoxy-6; 15/3,]GB-bismethylene-pregna-4-ene-3,20-dione. Melting point 199-201 C; e12,100 [a],,= 100 (c= 0.1 in dioxane).

EXAMPLE 12 A solution of 17,21-dihydroxy-15B,16B-methylene-pregna-4-ene-3,20-dione in 10 ml of pyridine and 10 ml of acetic anhydride waskept at room temperature for 30 minutes. The reaction mixture was workedup to yield 550 mg of 2l-acetoxy-l7a-hydroxy-15B,16B-methylene-pregna-4-ene-3,20-dione whichwas dissolved in a mixture of 15 m1 acetic acid, 4 ml of aceticanhydride and 550 mg of p-toluenesulfonic acid. The resulting mixturewas kept at room temperature for 2 hours, poured into ice water andextracted with methylene chloride. The organic extract afforded 660 mgof crude product which was chromatographed on silica gel. Usingmethylene chloride/acetone as the elution agent there was obtained 200mg of pure 3,17a,21-triacetoxy-l5fl,l6,B-methylene-pregna-- EXAMPLE 13Tablets suitable for oral administration were prepared according to thefollowing recipe.

wherein R is a B-keto-A a 3-keto-A a 3-keto-A system; R is hydrogen orhalogen; R is hydrogen, halogen, or lower alkyl; R is a hydroxy,acyloxy, or alkoxy group; R is hydrogen, halogen, hydroxy, acyloxy oralkoxy with the proviso that R is hydrogen when either R or R is otherthan hydrogen;

and both residues R in each case is hydrogen or methyl.

2. The compounds ofclaim 1 wherein R is hydrogen, that is,

compounds of the formula where R R R R n and R are as in claim 1. 3. Thecompounds ofclaim 2 wherein R is hydrogen, R, is a 3-keto-A'- A A or 13"system and R is hydrogen, that is,

compounds of the formula where R is as in claim 1, R is hydrogen orhalogen, V is a saturated or unsaturated bond between the l and 2positions and W is a saturated or unsaturated bond between the 6 and 7positions. 4. The compounds of claim 1 wherein R is methyl, that is,compounds of the formula where R R R R and R are as in claim 1.

5. The compounds of claim 2 wherein R and R are hydrogen and R isacyloxy.

6. The compound of claim 5 wherein R is a 3-keto A system; R is hydroxyand R is acetoxy, that is, 2l-acetoxyl7a-hydroxy-l 5B, 16B-methylene-pregna-4-ene-3 ,ZO-dione.

7. The compound of claim 5 wherein R is a 3-keto-A"- system and l t andR are acetoxy; that is,l7a,2l-diacetoxy-l53,16B-methylene-pregna-4-ene-3 ,ZO-dione.

8. The compounds of claim 2 wherein R and R are hydrogen and R ishydroxy.

9. The compound of claim 8 wherein R is a 3-ketoA"- system, and R ishydroxy, that is, l7a,2l-dihydroxy-l5 [3,1ofi-methylene-pregnai-ene-3,ZO-dione.

10. The compounds of claim 2 wherein R R and R are hydrogen and R is a3-acyloxy-A -system and R is acylox- 11. The compounds of claim 2wherein R and R are hydrogen, R is a 3-acyloxy-A -system and R and R areacyloxy.

12. The compound of claim 10 wherein R is a 3-acetoxy- A -system and Ris acetoxy, that is, 3,17a-diacetoxy-l5[3,16B-methylene-prcgna-3,S-dien-ZO-one.

13. The compound of claim 11 wherein R is a 3-acetoxy- A -system and Rand R are acetoxy, that is, 3,l7a,21-triacetoxy-15B,lfi'methylene-pregna-3,5-dien-20-one.

14. The compounds of claim 2 wherein R, is halogen.

15. The compound of claim 14 wherein R is chloro, R is a3-keto-A-system, R is hydrogen, R is acetoxy and R is hydrogen, that is,l7a-acetoxy-2/3-chloro-153,163- methylene-pregna-4-ene-3,20-dione.

16. The compounds of claim 4 wherein R is hydrogen, R is a 3-keto-A, A,A or N system and R is hydrogen, that 4 is, compounds of the formula R'sId where R is as in claim 1, R is hydrogen or halogen, V is a saturatedor unsaturated bond between the l and 2 positions and W is a saturatedor unsaturated bond between the 6 and 7 positions.

17. The compounds of claim 3 wherein R is hydroxy.

18. The compound of claim 17 wherein R is hydrogen, and V and W aresaturated bonds, that is, l7a-hydroxy'l5fi,l6B-methylene-pregna-4-ene-3,ZO-dione.

19. The compounds of claim 3 wherein R is acyloxy.

20. The compound of claim 19 wherein R is chloro, R is acetoxy and V andW are saturated bonds, that is, l7a-acetoxy 6fi-chloro- 1 5B, 16B-methylene-pregna-4ene-3,ZO-dione.

21. The compound of claim 19 wherein R, is chloro, Run is acetoxy, V isa saturated bond and W is an unsaturated bond, that is,l7a-acetoxy-6-chloro-l 5/3, 1 6B-methylene-pregna-4,6- diene-3 20-di0ne.

22. The compound of claim 19 wherein R is hydrogen, R

is acetoxy and V and W are saturated bonds, that is, 1711-acetoxy-l5B,1ofi-methylene-pregna-4-ene-3,ZO-dione.

23. The compound of claim 19 wherein R is hydrogen, R is acetoxy, V is asaturated bond and W is an unsaturated bond, that is,l7a-acetoxy-l5B,l6B-methylene-pregna-4,6- diene-3,20-dione.

24. The compounds of claim 2 wherein R is hydrogen, R is a 3-keto-A A Aor A"""-system, R is lower alkyl, R is acyloxy and R is hydrogen.

25. The compound of claim 24 wherein R is a 3-ketoA-- system, R ismethyl and R is acetoxy, that is l7a-acetoxy-6-methyl-15B,l6B-methylene-pregna-4,6diene-3 ,ZO-dione.

26. The compounds of claim 2 wherein R R and R are hydrogen and R is a3-alkoxy-A -system.

27. The compound of claim 26 wherein R is a 3-methoxy- N' -system, thatis, l7a-acetoxy-3-methoxy-158,163- methylene-pregna-3,5-dien-20-one.

28. Compounds of the formula CHzBn H30 (IIH Ra II where R is hydrogen ormethyl; R is hydrogen or halogen, R is hydrogen, halogen or lower alkyland R is hydrogen, halogen, hydroxy, acyloxy or alkoxy with the provisothat R is hydrogen when either R or R is other 2 21 IX mo (3:0

where R is hydrogen or methyl, R is hydrogen or halogen, R is a hydroxy,acyloxy or alkoxy group and R is hydrogen, halogen, hydroxy, acyloxy oralkoxy with the proviso that R,, is hydrogen when R, is other thanhydrogen. 33. The compounds of claim 32 wherein R, R, and R are hydrogenand R n is acyloxy.

34. The compound of claim 33, wherein R is acetoxy, that is,l7a-acetoxy-6;l5B,l6Bbismethylene-pregna-4-ene- 3,20 dione.

UNITED STATES PATENT OFFICE" QER'NFFCATE @F CURREECTIQN Patent o- 3 676,67- Dated I Jul 11, 1972 n t fls) .A'ndor Furst, Peter Muller, MarcelMuller 8:. Dieter Kagi 3 It is certified that error appears in theabove-identified patent 4 and that said Letters Patent are herebycorrected. as shown below:

Column 12, line 55, claim 3: "3 keto Abq?" should be 3 keto 4 Q Column13, line 18, claim 6: "pregna" should be .pregn Column 13, line 21,claim 7: "pregna" should be pregn Column 13, line 26 claim 9: "pregna"should be pregn Column 13, line 43, claim 15: "pregna' should be pregn"Column 13 line 66 claim 18: "pregna" should be pregn Column '13, line70, claim 20: "pregna" should be pregn Column 14, line 2 claim 21:"pi'egna" should be preg'n Column 14, line 6; c1aim 22: "pregna" shouldbe pregn Column 14 line 69 claim 34: "pregna" should be pregn Signed ands'ealed this 3rd day of July 1973.

(SEAL) Attest: v EDWARD M.FLETCHER,JR. Rene, 'Tesztmeyeu AttestingOfficer C g Commissioner of Patents l-ORM Po-wso (10-69) USCOMM'DC60375-P59 9 U.S. GOVERNMENT PRINTING OFFICE I919 0-365-32.

2. The compounds of claim 1 wherein R is hydrogen, that is, comPounds ofthe formula
 3. The compounds of claim 2 wherein R2 is hydrogen, R3 is a3-keto- Delta 4, Delta 1,4, Delta 4,6 or Delta 1,4,6 system and R21 ishydrogen, that is, compounds of the formula
 4. The compounds of claim 1wherein R is methyl, that is, compounds of the formula
 5. The compoundsof claim 2 wherein R2 and R6 are hydrogen and R21 is acyloxy.
 6. Thecompound of claim 5 wherein R3 is a 3-keto Delta 4 system; R17 ishydroxy and R21 is acetoxy, that is, 21-acetoxy-17 Alpha -hydroxy-15Beta ,16 Beta -methylene-pregna-4-ene-3,20-dione.
 7. The compound ofclaim 5 wherein R3 is a 3-keto- Delta 4-system and R17 and R21 areacetoxy; that is, 17 Alpha ,21-diacetoxy-15 Beta ,16 Beta-methylene-pregna-4-ene-3,20-dione.
 8. The compounds of claim 2 whereinR2 and R6 are hydrogen and R21 is hydroxy.
 9. The compound of claim 8wherein R3 is a 3-keto Delta 4-system, and R17 is hydroxy, that is, 17Alpha ,21-dihydroxy-15 Beta ,16 Beta -methylene-pregna-4-ene-3,20-dione.10. The compounds of claim 2 wherein R2, R6 and R21 are hydrogen and R3is a 3-acyloxy- Delta 3,5-system and R17 is acyloxy.
 11. The compoundsof claim 2 wherein R2 and R6 are hydrogen, R3 is a 3-acyloxy- Delta3,5-system and R17 and R21 are acyloxy.
 12. The compound of claim 10wherein R3 is a 3-acetoxy- Delta 3,5-system and R17 is acetoxy, that is,3,17 Alpha -diacetoxy-15 Beta ,16 Beta-methylene-pregna-3,5-dien-20-one.
 13. The compound of claim 11 whereinR3 is a 3-acetoxy- Delta 3, 5-system and R17 and R21 are acetoxy, thatis, 3,17 Alpha ,21-triacetoxy-15 Beta ,16 Beta-methylene-pregna-3,5-dien-20-one.
 14. The compounds of claim 2 whereinR2 is halogen.
 15. The compound of claim 14 wherein R2 is chloro, R3 isa 3-keto- Delta 4-system, R6 is hydrogen, R17 is acetoxy and R21 ishydrogen, that is, 17 Alpha -acetoxy-2 Beta -chloro-15 Beta ,16 Beta-methylene-pregna-4-ene-3,20-dione.
 16. The compounds of claim 4 whereinR2 is hydrogen, R3 is a 3-keto- Delta 4, Delta 1,4, Delta 4,6 or Delta1,4,6 system and R21 is hydrogen, that is, compounds of the formula 17.The compounds of claim 3 wherein R17 is hydroxy.
 18. The compound ofclaim 17 wherein R6'' is hydrogen, and V and W are saturated bonds, thatis, 17 Alpha -hydroxy-15 Beta ,16 Beta-methylene-pregna-4-ene-3,20-dione.
 19. The compounds of claim 3 whereinR17 is acyloxy.
 20. The compound of claim 19 wherein R6'' is chloro, R17is acetoxy and V and W are saturated bonds, that is, 17 Alpha -acetoxy 6Beta -chloro-15 Beta ,16 Beta -methylene-pregnA-4-ene-3,20-dione. 21.The compound of claim 19 wherein R6'' is chloro, R17 is acetoxy, V is asaturated bond and W is an unsaturated bond, that is, 17 Alpha-acetoxy-6-chloro-15 Beta ,16 Beta-methylene-pregna-4,6-diene-3,20-dione.
 22. The compound of claim 19wherein R6'' is hydrogen, R17 is acetoxy and V and W are saturatedbonds, that is, 17 Alpha -acetoxy-15 Beta ,16 Beta-methylene-pregna-4-ene-3,20-dione.
 23. The compound of claim 19 whereinR6'' is hydrogen, R17 is acetoxy, V is a saturated bond and W is anunsaturated bond, that is, 17 Alpha -acetoxy-15 Beta ,16 Beta-methylene-pregna-4,6-diene-3,20-dione.
 24. The compounds of claim 2wherein R2 is hydrogen, R3 is a 3-keto- Delta 4 , Delta 1,4 , Delta 4,6or Delta 1,4,6-system, R6 is lower alkyl, R17 is acyloxy and R21 ishydrogen.
 25. The compound of claim 24 wherein R3 is a 3-keto Delta4,6-system, R6 is methyl and R17 is acetoxy, that is 17 Alpha-acetoxy-6-methyl-15 Beta ,16 Beta -methylene-pregna-4,6-diene-3,20-dione.
 26. The compounds of claim 2 wherein R2, R6 and R21 arehydrogen and R3 is a 3-alkoxy- Delta 3,5-system.
 27. The compound ofclaim 26 wherein R3 is a 3-methoxy- Delta 3, 5-system, that is, 17 Alpha-acetoxy-3-methoxy-15 Beta ,16 Beta -methylene-pregna-3,5-dien-20-one.28. Compounds of the formula
 29. The compounds of claim 28 wherein R ishydrogen.
 30. The compound of claim 29 wherein R2, R6 and R21 arehydrogen, that is, 15 Beta ,16 Beta-methylene-pregna-4,17(20)-dien-3-one.
 31. The compound of claim 29wherein R2 and R6 are hydrogen and R21 is acetoxy, that is,21-acetoxy-15 Beta ,16 Beta -methylene-pregna-4,17(20)-dien-3-one. 32.Compounds of the formula
 33. The compounds of claim 32 wherein R, R2 andR21 are hydrogen and R17 is acyloxy.
 34. The compound of claim 33,wherein R17 is acetoxy, that is, 17 Alpha -acetoxy-6;15 Beta ,16 Beta-bismethylene-pregna-4-ene-3,20-dione.